In particle forming processes there has been developed methods using supercritical fluids. Three types of these methods can be distinguished:                Rapid Expansion of Supercritical Solutions (RESS): This process consists in solvating the solute in the supercritical fluid and rapidly depressuring this solution through an adequate nozzle, causing an extremely rapid nucleation of the compound into a highly dispersed material. This process is attractive due to the absence of organic solvent use but is restricted to compounds with a reasonable solubility in the supercritical fluid.        Gas-Anti-Solvent precipitation (GAS), or Supercritical fluid Anti-Solvent: The processes generally comprise a solute dissolved in a conventional solvent called the vehicle system (solute+solvent). The vehicle is extracted by the supercritical fluid whereby extraction and droplet formation occurs simultaneously.        Modification of GAS: ASES—This name is rather used when micro- or nano-particles are expected. The process consists of pulverizing a solution of the solute in an organic solvent into a vessel swept by a supercritical fluid SEDS (Solution Enhanced Dispersion by Supercritical fluids)—This is a specific implementation of ASES and consists of co-introducing the vehicle with a flow of supercritical fluid in a mixing chamber in the spraying nozzle.        
In all these processes it is important to maintain control over the working conditions especially the pressure. To be able to eliminate pressure fluctuations is vital for obtaining the desired particle size and size distribution as well as avoiding agglomeration.
A supercritical fluid can be defined as a fluid at or above its critical pressure and critical temperature simultaneously. The use of supercritical fluids and the properties thereof is described e.g. in J. W. Tom and P. G. Debendetti “Particle Formation with Supercritical Fluids—A Review”, J. Aerosol Sci 22 (50.554-584 (1991). Such fluids are interesting in particle formation since their solving power of different substances undergoes large changes as a result of changes in the physical characteristics of the surroundings, which characteristics can be relatively easily controlled, such as pressure. This property make supercritical fluid a medium highly appreciated for having a solving power being controllable by pressure and temperature changes, which is particularly useful in extraction and atomization of different substances, such as substances used in pharmacy. Further, supercritical fluids are normally gases under ambient condition, which eliminates the evaporation step needed in conventional liquid extraction.
In document WO 95/01221 the nozzle is designed for co-introduction of the vehicle and the supercritical fluid into the particle formation vessel. The nozzle has coaxial passages to carry the flow of the vehicle system and of the supercritical flow. The two are mixed in a particle formation chamber which is conical at an angle of taper typically in the range of 10 to 50 degrees. An increase in the angle may be used for increasing the velocity of the supercritical fluid introduced into the nozzle and hence the amount of physical contact between the supercritical fluid and the vehicle system. Control of parameters such as size and shape in the resulting product will be dependent upon variables including the flow rates of the supercritical fluid and/or the vehicle system, the concentration of the substance in the vehicle system, the temperature and pressure inside the particle formation vessel and the nozzle orifice diameter.
A further step to intensify the mixing between the vehicle system and the supercritical fluid in a mixing chamber is described in the document WO 00/67892. In this invention turbulence is introduced in at least one of the fluid gas or the vehicle system so as to create a controlled disorder in the flow of at least one of the fluid gas or vehicle system in order to control the particle formation in the mixing chamber.
In another patent document, WO96/00610, the method is improved by introducing a second vehicle, which is both substantially miscible with the first vehicle and substantially soluble in the supercritical fluid. The corresponding apparatus is consequently provided with at least three coaxial passages. These passages terminate adjacent or substantially adjacent to one another at the outlet end of the nozzle, which end is communicating with a particle formation vessel. In one embodiment of the nozzle the outlet of at least one of the inner nozzle passages is located a small distance upstream (in use) of the outlet of one of its surrounding passages. This allows a degree of mixing to occur within the nozzle between the solution or suspension, that is the first vehicle system, and the second vehicle. This pre-mixing of the solution and the second vehicle does not involve the supercritical fluid. It is in fact believed that the high velocity supercritical fluid emerging from the outer passage of the nozzle causes the fluids from the inner passages to the broken up into fluid elements. From these fluid elements the vehicles are extracted by the supercritical fluid, which results in the formation of particles of the solid previously solved in the first vehicle. The useful maximal taper of the conical end is in this document also augmented up to 60 degrees.
Another technique for particle precipitation using near-critical and supercritical antisolvents has later been described in WO97/31691. This document mentions the use of specialized nozzles for creating extremely fine droplet sprays of the fluid dispersions. The method involves passing the fluid dispersion through a first passageway and a first passageway outlet into a precipitation zone, which contains an antisolvent in near- or supercritical condition. Simultaneously an energizing gas stream is passed along and through a second passageway outlet proximal to the first fluid dispersion outlet. The passage of the energizing gas stream generates high frequency waves of the energizing gas adjacent to the first passageway outlet in order to break up the fluid dispersion into small droplets
WO 03/008082 discloses a device where the first and second conduit means meet each other at the mixing means at an angle of about 90°. The two jets coming from the conduits meet each other in a free open space.
Other examples of devices and methods in this field are disclosed in WO98/36825, WO99/44733, WO99/59710, WO99/12009, WO01/03821, WO01/15664, WO02/38127, WO95/01221, WO01/03821, WO98/36825, PCT GB2003/001665 and PCT GB2003/001747.
Prior art of producing small particles by use of supercritical fluids as anti-solvents try to achieve control over pressure, temperature and flow in order to control morphology, size and size-distribution of the particles formed. The need from e.g. the pharmaceutical industry for small particles with desired size distribution and morphology do, however, invoke the need for better particle formation techniques than those mentioned in the disclosed prior art. This is of particular interest in creating particles in the nanometer size range. Commonly encountered problems with existing particle formation designs (nozzle designs) are clogging of the opening of the nozzle by particle agglomerates and inability to produce particles in the submicron range. Particles formed in the nanometer size range by existing techniques all show poor control of particle size distribution as well as poor crystallinity resulting in poor physical stability (recrystallization and particle growth). Furthermore, the use of exotic solvents like DMSO as well as emulsifiers which have limited use in large scale production have been used to obtain sub-micron particles.
The object of the present invention is to overcome the drawbacks entailing methods and devices according to prior art. More specifically the object is to obtain particles of higher quality regarding size distribution, surface structure and morphology and to allow formation of articles of a size that up to know haven't been possible or only with difficulty, i.e. particles of a size less than 1 μm.